Abstract
BackgroundThere is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Using data from large, extended families of Mexican Americans (a high-risk minority population in the USA) we aimed to: (1) estimate the prevalence of this phenotype, (2) test its association with T2D and related traits, and (3) dissect out the genetic and epigenetic associations with this phenotype using genome-wide and epigenome-wide studies, respectively.ResultsData for this study was from 850 Mexican American participants (representing 39 families) recruited under the ongoing San Antonio Family Heart Study, 26 % of these individuals had HTGW. This phenotype was significantly heritable (h2r = 0.52, p = 1.1 × 10−5) and independently associated with T2D as well as fasting glucose levels and insulin resistance. We conducted genome-wide association analyses using 759,809 single nucleotide polymorphisms (SNPs) and epigenome-wide association analyses using 457,331 CpG sites. There was no evidence of any SNP associated with HTGW at the genome-wide level but two CpG sites (cg00574958 and cg17058475) in CPT1A and one CpG site (cg06500161) in ABCG1 were significantly associated with HTGW and remained significant after adjusting for the closely related components of metabolic syndrome. CPT1A holds a cardinal position in the metabolism of long-chain fatty acids while ABCG1 plays a role in triglyceride metabolism.ConclusionsOur results reemphasize the value of HTGW as a marker of T2D. This phenotype shows association with DNA methylation within CPT1A and ABCG1, genes involved in fatty acid and triglyceride metabolism. Our results underscore the importance of epigenetics in a clinically informative phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0173-x) contains supplementary material, which is available to authorized users.
Highlights
There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease
To ensure that the potential association of genetic and epigenetic variants with HTGW is not confounded by the presence of comorbidities, we used robust statistical models that accounted for the simultaneous presence of comorbidities in our analyses
Our study reports several novel findings: (1) the prevalence of HTGW in our sample of Mexican Americans is ~26 %; (2) HTGW is a significant independent predictor of T2D as well as fasting glucose, insulin levels and insulin resistance; (3) HTGW is significantly heritable; (4) DNA methylation within the 5’UTR region of CPT1A and in the gene body of ATP binding cassette G1 (ABCG1) is significantly associated with HTGW, independent of related comorbidities; (5) methylation at the top three significantly associated CpG sites together account for 9.52 % of the variability of HTGW, which is unlikely to be due to surrounding sequence variants
Summary
There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (≥95 cm in males and ≥80 cm in females) combined with high serum triglyceride concentration (≥2.0 mmol/L in males and ≥1.5 mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. The prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored. Given the possibility of a significant environmental influence (e.g., through diet and physical activity) on both waist circumference and triglyceride levels [11, 17, 18], it is conceivable that the HTGW phenotype may be epigenetically modifiable. Recent elegant studies have shown promising results for the association of DNA methylation separately with waist circumference [19,20,21] and triglyceride levels [22,23,24], to our knowledge, currently, there are no studies on the possible epigenetic role in the interindividual variability in HTGW
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